CD117 (c-kit proto-oncogene)

The c-kit proto-oncogene codes for a 145 to 160 kDa type III transmembrane tyrosine kinase receptor protein, structurally and functionally closely related to platelet-derived growth factor and macrophage colony stimulating factor. The gene has been mapped to chromosome 4q11-12. The protein product, KIT, is the receptor for stem cell factor (mast cell growth factor). The ligand is an early haemopoietic growth factor, which is also required for the development of germ cells and melanocytes2. Loss of gene function during embryogenesis results in white spotting in mice and humans. The c-kit proto-oncogene is the cellular counterpart of the transforming gene of the Hardy-Zuckerman feline sarcoma virus19. There is homology to PDGF and colony stimulating factor19. Ligand binding results in dimerisation and phosphorylation of specific tyrosine residues. These phosphorylated sites in turn act as docking sites for signal transduction molecules , which themselves become phosphorylated and are often themselves kinases19.

The antisera available to date are polyclonal and are effective on paraffin-embedded tissue11.

The tyrosine kinase inhibitor STI-571 binds to the ATP enzymatic binding pocket of the tyrosine kinases c-abl, PDGF and c-kit. It is used to inhibit c-abl for the treatment of CML. There are results from Phase I and II trials that indicate that the tyrosine kinase inhibitor STI-571, by inhibiting c-kit, may be highly efficacious in the treatment of GISTs5. There is, as yet, no data to support a role for STI-571 in the treatment of other solid tumours which may express strong CD117 positivity (adenoid cystic carcinoma, seminoma, small cell lung carcinoma)6. STI-571 is likely to be less efficacious in tumours that have a mutation in exon 17 at codon 816, replacing aspartate with valine and so modifying the the tyrosine kinase binding pocket19.

Immunohistochemical expression

Normal tissues2:

Organ

tissue

nature of staining

general

mast cells

strong, membrane and cytoplasmic8

endothelium

weak, cytoplasmic

brain

glial cell, Purkinje cells

 

moderate, cytoplasmic

breast

ductal epithelium

stomach

parietal cells

kidney

renal tubules

moderate in proximal and weak in distal tubules, cytoplasmic, loop of Henle moderate, collecting ducts negative13

ovary

stroma and follicles

moderate, cytoplasmic

oocytes

moderate to strong, cytoplasm and membrane

corpus luteum

weak, cytoplasmic

testis

seminiferous tubules, germ cells

moderate to strong, cytoplasm and membrane

skin

melanocytes

moderate, cytoplasm10

immature Langerhans' cells

positive10

epidermal basal cells

positive8,10

gallbladder

epithelium

 

weak, cytoplasm

bladder

mucosa

prostate

some basal cells

thyroid

follicle epithelium

eye

cornea and retina

positivity reported

salivary gland

ducts and acinar cells

adrenal

medulla

small intestinal mucosa8

 

 

none

colonic mucosa8

liver

pancreas8

lymph node

peripheral nervous system8

endocervical glandular epithelium8

myometrium

Tumours:

 

n

negative

weak

moderate

strong

mast cell disease

11

 

 

 

11, 22/227

breast, invasive ductal carcinoma

47

28

13

6

0

breast, lobular carcinoma

3

3

0

0

0

breast, DCIS

2

0

2

0

0

lung, adenocarcinoma

34

8

22

4

0

Tsuura reported positivity in 8/144 non small cell carcinoma of the lung3

lung, squamous cell carcinoma

21

6

15

0

0

Tsuura reported positivity in 45/123 small cell carcinoma of the lung3

Mojica reported positivity in 23/40 small cell carcinomas of lung: none of the 11 cases examined by PCR showed point mutations at codon 81619.

lung, small cell carcinoma

7

1

2

3

1

extrapulmonary small cell carcinoma

4

0

2

2

0

lung, clear cell carcinoma

1

1

0

0

0

mesothelioma

50

37

12

1

0

oesophagus, squamous cell carcinoma

5

1

4

0

0

stomach, adenocarcinoma

1

1

0

0

0

colon, adenocarcinoma

30

23

6

1

0

pancreas, adenocarcinoma

14

6

6

2

0

pancreas, islet cell tumour

1

0

1

0

0

liver, hepatocellular carcinoma

3

1

2

0

0

bladder, transitional cell carcinoma

24

9

14

1

0

prostate, adenocarcinoma

29

23

6

0

0

renal cell carcinoma NOS

28

28

0

0

0

conventional renal cell carcinoma

1313

1113, 6/618

013

113

113

papillary renal cell carcinoma

713

513

113

113

013

chromophobe renal cell carcinoma

713

313

313

113

013, 11/1118

renal nephroblastoma

613

613

013

013

013

renal oncocytoma

713

013

213

213

313, 12/1218

mesoblastic nephroma

213

013

013

113

113

angiomyolipoma

413, 2120

213

013, 320

213, 420

013, 1420

endometrium, hyperplasia

2

0

2

0

0

endometrium, adenocarcinoma

8

0

7

1

0

ovary, serous carcinoma

16

1

4

7

3

ovary, clear cell carcinoma

2

2

0

0

0

ovary, poorly differentiated carcinoma

5

0

3

2

0

thyroid, hyperplasia

1

1

0

0

0

thyroid, Hashimoto's

1

1

0

0

0

thyroid, adenoma

2

2

0

0

0

thyroid, follicular carcinoma

11

0

11

0

0

thyroid, papillary carcinoma

9

0

7

2

0

thyroid, medullary carcinoma

7

7

0

0

0

thyroid, anaplastic carcinoma

1

1

0

0

0

adnexal adenoid cystic carcinoma

1

0

0

0

1

malignant melanoma

40

4

30

4

2

lymphoma

49

42

6

1

0

brain, glioma

6

1

4

1

0

testicular embryonal carcinoma

7

0

7

0

0

testicular yolk sac tumour

3

0

3

0

0

testicular seminoma

5

0

2

3

0

Tian reported typical cell membrane positivity in 23/23 seminomas/dysgerminomas17

liposarcoma

3

3

0

0

0

leiomyosarcoma

6

2

4

0

0

angiosarcoma

1

0

1

0

0

Ewing's sarcoma

1

1

0

0

0

alveolar soft part sarcoma

1

1

0

0

0

clear cell sarcoma

10

5

5

0

0

epithelioid sarcoma

10

5

5

0

0

rhabdomyosarcoma

5

2

3

0

0

synovial sarcoma

8

1

6

1

0

sarcoma NOS

23

9

14

0

0

 

 

 negative

weak

moderate

strong

Total

576

271

244

43

18

 

benign phyllodes tumour

17/101 (17%)15

  

borderline phyllodes tumour

12/50 (24%)15

malignant phyllodes tumour

13/28 (46%)15
   

 

CD117 is NOT expressed by:

Expression of CD117 and CD34 appears to be reduced in chronic intestinal pseudo-obstruction, indicating that this syndrome may be due to loss of the interstitial cells of Cajal and their pacemaker function12.

Diagnostic utility

The diagnostic utility is limited by the wide range of tissues in which CD117 is expressed:

References

1 Bates AW, Feakins RM, Scheimberg I. Congenital gastrointestinal stromal tumour is morphologically indistinguishable from the adult form. but does not express CD117 and carries a favourable prognosis. Histopathology 2000;37:316-322.

2 Arber DA et al. Paraffin section detection of the c-kit gene product (CD117) in human tissues: value in the diagnosis of mast cell disorders. Hum Pathol 1998;28:498-504.

3 Tsuura Y et al. Preferential localization of c-kit product in tissue mast cells of skin, epithelial cells of breast, small cell lung carcinoma and seminoma/dysgerminoma in human: immunohistochemical study on formalin-fixed, paraffin-embedded tissues. Virchows Archiv A Pathol Anat 1994;424:135-141.

4 JF Graadt van Roggen et al. The histopathological differential diagnosis of gastrointestinal stromal tumours. J Clin Pathol 2001; 54: 96-103.

5 Advances in Anatomic Pathology (news in brief) 2001;8:304.

6 Berman, J., O'Leary, T. J. Gastrointestinal stromal tumor workshop Human Pathol 2001; 32:578-582.

7 Jordan, J. H., Walchshofer, S., Jurecka, W., Mosberger, I., Sperr, W. R., Wolff, K., Chott, A., Buhring, H. J., Lechner, K., Horny, H. P., Valent, P. Immunohistochemical properties of bone marrow mast cells in systemic mastocytosis: evidence for expression of CD2, CD117/Kit, and bcl-x(L) Hum Pathol 2001;32:545-552.

8 Gibson, P. C., Cooper, K. CD117 (KIT): a diverse protein with selective applications in surgical pathology. Adv Anat Pathol 2002;9:65-69.

9 Sabah M, Cummins R, Leader M. Immunohistochemical detection of CD117 expression in soft tissue sarcomas. Pathological Society, July 2002, abstract no 49.

10 JF Graadt van Roggen et al. The histopathological differential of diagnosis of gastrointestinal stromal tumours. J Clin Pathol 2001; 54: 96-102.

11 Leong A S-Y, Cooper K and Leong FJ W-M. Manual of diagnostic antibodies for immunohistology. 2nd edition, 2003

12 Streutker, C.J., Huizinga, J.D., Campbell, F., Ho, J. and Riddell, R.H. Loss of CD117 (c-kit)- and CD34-positive ICC and associated CD34- positive fibroblasts defines a subpopulation of chronic intestinal pseudo-obstruction. Am J Surg Pathol 2003;27:228-35.

13 Miliaras, D., F. Karasavvidou, et al. (2004). "KIT expression in fetal, normal adult, and neoplastic renal tissues." J Clin Pathol 57(5): 463-466.

14 Petit, A., M. Castillo, et al. (2004). "KIT Expression in Chromophobe Renal Cell Carcinoma: Comparative Immunohistochemical Analysis of KIT Expression in Different Renal Cell Neoplasms." Am J Surg Pathol 28(5): 676-678.

15 Tse, G. M., T. C. Putti, et al. (2004). "Increased c-kit (CD117) expression in malignant mammary phyllodes tumors." Mod Pathol 17(7): 827-31.

16 Ramalingam, P., A. Malpica, et al. (2004). "The use of cytokeratin 7 and EMA in differentiating ovarian yolk sac tumors from endometrioid and clear cell carcinomas." Am J Surg Pathol 28(11): 1499-1505.

17 Tian, Q., H. F. Frierson, Jr., et al. (1999). "Activating c-kit gene mutations in human germ cell tumors." Am J Pathol 154(6): 1643-7.
 FULL TEXT

18 Wang HY,Mills SE. KIT and RCC are useful in distinguishing chromophobe renal cell carcinoma from the granular variant of clear cell renal cell carcinoma. Am J Surg Pathol 2005; 29:640-6

19 Mojica WD, Saxena R, Starostik P, et al. CD117+ small cell lung cancer lacks the asp 816-->val point mutation in exon 17. Histopathology 2005; 47:517-22

20 Makhlouf HR, Remotti HE,Ishak KG. Expression of KIT (CD117) in angiomyolipoma. Am J Surg Pathol 2002; 26:493-7

 

This page last revised 2.5.2006.

©SMUHT/PW Bishop